title: Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.
abstract: BACKGROUND
  Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.
  
  
  OBJECTIVE
  To determine how mitochondria impact endothelial cell function.
  
  
  RESULTS
  We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Δψ) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype.
  
  
  CONCLUSIONS
  These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Medicine.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Shimasaki
authors.forename: Ning
authors.initials: N
authors.lastname: Pan
authors.forename: Louis M
authors.initials: LM
authors.lastname: Messina
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
authors.forename: Marcus P
authors.initials: MP
authors.lastname: Cooper
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vita
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002417:Cattle; D049109:Cell Proliferation; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D013481:Superoxides
keywords: angiogenesis; endothelial function; endothelium; ischemia; mitochondria; mitochondrial uncoupling proteins; superoxides